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ABSTRACT
Background The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as anticonvulsant embryopathy, is increased in infants exposed to anticonvulsant
drugs in utero. However, whether the abnormalities
are caused by the maternal epilepsy itself or by exposure to anticonvulsant drugs is not known.
Methods We screened 128,049 pregnant women
at delivery to identify three groups of infants: those
exposed to anticonvulsant drugs, those unexposed
to anticonvulsant drugs but with a maternal history
of seizures, and those unexposed to anticonvulsant
drugs with no maternal history of seizures (control
group). The infants were examined systematically for
the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and
small body size.
Results The combined frequency of anticonvulsant
embryopathy was higher in 223 infants exposed to
one anticonvulsant drug than in 508 control infants
(20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency was
also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent
vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence
interval, 1.1 to 5.1). The 98 infants whose mothers had
a history of epilepsy but took no anticonvulsant drugs
during the pregnancy did not have a higher frequency of those abnormalities than the control infants.
Conclusions A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during
pregnancy, rather than with epilepsy itself. (N Engl J
Med 2001;344:1132-8.)
Copyright 2001 Massachusetts Medical Society.
had epilepsy but took no anticonvulsant drugs during the pregnancy, and those whose mothers had no
history of epilepsy and took no anticonvulsant drugs
during the pregnancy (the control group).
METHODS
Study Design
This study was conducted from 1986 to 1993 at five maternity
hospitals in the Boston area: Brigham and Womens Hospital, Beth
Israel Hospital, St. Margarets Hospital, St. Elizabeths Hospital,
and NewtonWellesley Hospital. Potential subjects were identified
in the labor and delivery suites by nurses who asked the women
if they had taken any medication for seizures during the pregnancy
and if they had ever had a seizure.13 Women who answered yes to
either question were then interviewed, with the approval of their
obstetricians and nurses, to inform them about the study and to
determine whether they qualified for inclusion. Women were excluded if they did not speak English, had a multiple-gestation pregnancy, or had another potentially teratogenic factor, such as type
1 diabetes mellitus. If the women qualified, they were asked to
enroll and to give written informed consent. The study protocol
was reviewed and approved annually by the institutional review
board at each participating hospital. If a mother chose not to enroll, the results of the pediatricians examination of her infant were
reviewed to obtain birth weight, length, head circumference, and
the presence or absence of any major malformations; these infants
were not examined by a study physician.
The women enrolled in the study were asked to provide demographic data and to complete questionnaires administered by a research assistant to determine why they were taking anticonvulsant
drugs (e.g., epilepsy or bipolar disorder); the dosage of each anticonvulsant drug; the characteristics of the seizures, their frequency
during the pregnancy, and whether the women lost consciousness
during seizures; and the family history with respect to epilepsy.
With the written authorization of each woman, the results of all
diagnostic tests (e.g., magnetic resonance images, electroencephalograms, and skull radiographs) and the dosages and serum concentrations of any anticonvulsant drugs were obtained. The responses to the questions and the results of the diagnostic evaluations
of the women were reviewed by the study epileptologist to determine the type of epilepsy and its apparent cause with the use of
an international classification of epilepsy.14
For each of the infants born to the enrolled women (i.e., either
an infant exposed to anticonvulsant drugs or an infant not exposed to anticonvulsant drugs whose mother reported having had
epilepsy), a control was recruited from the 10 infants born closest
in time to him or her. Selecting randomly from this group of infants, we approached each mother until one was enrolled for each
index infant. The same questionnaire was administered to the mothers of the control infants, with a separate consent form.
Examination of the Infants
The infants in all three groups were examined by a study physician; this physician was unaware of the exposure status of the
From the Genetics and Teratology Unit, Pediatric Service, Massachusetts
General Hospital (L.B.H., E.A.H., K.B.H., A.M.H.); the Department of
Biostatistics, Harvard School of Public Health (B.A.C., L.M.R.); and the
Department of Neurology, Brigham and Womens Hospital (S.K.) all in
Boston. Address reprint requests to Dr. Holmes at the Genetics and Teratology Unit, Warren 801, Massachusetts General Hospital, 55 Fruit St.,
Boston, MA 02114-2696, or at holmes.lewis@mgh.harvard.edu.
1132 N Engl J Med, Vol. 344, No. 15 April 12, 2001 www.nejm.org
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RESULTS
By screening 128,049 women in labor and delivery suites, we identified 509 who had taken one or
more anticonvulsant drugs during pregnancy, 386 of
whom had taken one drug and 123 of whom had taken two or more drugs (30 women who had switched
from one drug to another were included in the latter
group) (Table 2). Among the 386 women who had
EXAMPLE
Physical features at birth that are normally present before 37 weeks of gestation
Findings on prenatal ultrasonography but
not on physical examination
Genetic disorders
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CATEGORY
INFANTS WITH
A MATERNAL
HISTORY OF
INFANTS
SEIZURES NOT
EXPOSED TO
EXPOSED TO
ANTICONVUL- ANTICONVUL- CONTROL
SANT DRUGS
SANT DRUGS
INFANTS
number of infants
Identified
Excluded because maternal history
of epilepsy involved childhood
febrile seizures only
Ineligible for participation
Death of infant
NonEnglish-speaking mother
Multiple birth
Sibling of a previously enrolled
infant
Exposure to other teratogens
Eligible for participation
Not examined
Obstetrician or nurse refused*
Mother refused
Mother was discharged sooner
than expected
Potential enrollees
Excluded because maternal condition
was not epilepsy or the episodes
were not true seizures
Singleton infants examined
VARIABLE
ANTICONVULSANT
DRUGS DURING
PREGNANCY
(N=316)
NO ANTICONVULSANT
DRUGS DURING
PREGNANCY
(N=98)
no. (%)
62
146
56
8
11
7
(20.3)
(47.7)
(18.3)
(2.6)
(3.6)
(2.3)
27
45
21
0
4
0
(27.6)
(45.9)
(21.4)
509
0
606
183
1186
0
7
14
28
23
5
24
12
29
8
54
53
0
7
430
4
349
27
1044
11
73
30
13
119
50
67
438
31
316
0
167
69
508
0
*Twenty women were classified as having episodes that were not true seizures, and eight women could not be interviewed. Because of rounding, not
all percentages total 100.
508
More than one possible cause was present for several women; apparent
causes were established for 306 of the 316 women who received anticonvulsant drugs during pregnancy.
316
98
*When the obstetrician or the nurse was asked by the research assistant
if she could approach the mother to describe the study, either the obstetrician or the nurse said that the mother should not be approached.
Types of epilepsy
Simple partial
Complex partial
Absence
Generalized
Juvenile myoclonic
Total
14 (4.6)
2 (0.6)
306
40
204
0
40
4
288
(13.9)
(70.8)
(13.9)
(1.4)
(4.1)
3 (3.1)
0
100
17
62
1
16
2
98
(17.3)
(63.3)
(1.0)
(16.3)
(2.0)
The type of epilepsy was established for 288 of the 316 women.
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3/58 (5.2)
3.0 (0.616)
8/58 (13.8)
2.4 (0.89.1)
1.07.7
11/87 (12.6)
2.1 (0.99.3)
0.96.8
18/87 (20.7)
8/58 (13.8)
2.8 (1.18.8) 1.7 (0.44.6)
1.37.2
0.65.0
0/46 (0.0)
2/38 (5.3)
9/74 (12.2)
1/63 (1.6)
3/62 (4.8)
3/64 (4.7)
2.7 (0.616.4)
PHENOBARBITAL
16/148 (10.8)
20/223 (9.0)
2.3 (1.06.9)
1.17.1
8/221 (3.6)
8/219 (3.7)
10/223 (4.5)
2.6 (0.88.3)
TOTAL
14/184 (7.6)
5/52 (9.6)
26/93 (28.0)
4.2 (1.15.1)
1.57.6
6/76 (7.9)
21/93 (22.6)
4.3 (1.415.6)
1.811.9
7/55 (12.7)
14/93 (15.1)
4.1 (1.317.5)
1.919.3
7/92 (7.6)
3/90 (3.3)
8/93 (8.6)
5.1 (1.021.1)
INFANTS EXPOSED TO
TWO OR MORE ANTICONVULSANT DRUGS
72/316 (22.8)
3.2 (1.35.0)
1.54.8
20/260 (7.7)
57/316 (18.0)
3.3 (1.67.2)
1.66.1
23/203 (11.3)
34/316 (10.8)
2.9 (1.27.1)
1.47.5
15/313 (4.8)
11/309 (3.6)
18/316 (5.7)
3.3 (0.98.3)
7/46 (15.2)
6/58 (10.3)
7/64 (10.9)
2.7 (0.913.4) 2.9 (0.813.4)
0.914.1
0.811.2
3/57 (5.3)
2/56 (3.6)
IN
7/53 (13.2)
4/87 (4.6)
1.1 (0.27.1)
0.35.9
2/87 (2.3)
1/87 (1.1)
3/87 (3.4)
1.9 (0.39.2)
TO A
SELECTED OUTCOMES
CARBAMAZEPINE
INFANTS EXPOSED
PHENYTOIN
OF
6/98 (6.1)
0.7 (0.22.4)
0.32.7
2/83 (2.4)
5/98 (5.1)
0.8 (0.23.4)
0.33.0
2/70 (2.9)
3/98 (3.1)
0.8 (0.14.5)
0.13.7
2/97 (2.1)
2/96 (2.1)
0/98 (0.0)
UNEXPOSED INFANTS
BORN TO WOMEN
WITH A HISTORY
OF SEIZURE
43/508 (8.5)
1.0
11/471 (2.3)
32/508 (6.3)
1.0
13/339 (3.8)
21/508 (4.1)
1.0
6/508 (1.2)
8/508 (1.6)
9/508 (1.8)
1.0
UNEXPOSED INFANTS
BORN TO WOMEN
WITH NO HISTORY
OF SEIZURE
(CONTROLS)
Values were based on the presence of arch patterns on at least six fingers, stiff interphalangeal joints, or both.
**These values were based on the length of the upper lip, the length of the nose, and the inner canthal distance; if two out of three measurements were more than 1 SD from the mean, midface hypoplasia was
considered to be present.
Values were adjusted for cigarette and alcohol use, substance abuse, severity of seizures, and head circumference and height of the mother.
These values were based on data from infants born in Halifax, Nova Scotia.17
P0.05 after adjustment for multiple comparisons with a control with use of Dunnetts multiple-comparison procedure.20
Values were adjusted for cigarette and alcohol use, substance abuse, and severity of seizures.
Major malformations did not include genetic disorders, positional deformities or deformations, and minor anomalies and features found on prenatal ultrasonography but not on physical examination.
*The controls (the unexposed infants born to women with no history of seizure) formed the comparison group in the calculation of the odds ratios. CI denotes confidence interval.
Midface hypoplasia**
No./total no. (%)
Major malformations, microcephaly, growth retardation, and midface hypoplasia (one or more)
No./total no. (%)
Odds ratio (95% CI)
95% CI of the generalized estimating equation
Growth retardation
No./total no. (%)
Major malformations, microcephaly, and growth
retardation (one or more)
No./total no. (%)
Odds ratio (95% CI)
95% CI of the generalized estimating equation
Microcephaly
No./total no. (%)
Major malformations
No./total no. (%)
Odds ratio (95% CI)
OUTCOMES
TABLE 4. FREQUENCY
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MALFORMATIONS*
Phenytoin
enrolled and examined as part of the study and 536 infants who were not enrolled in the frequency of major
malformations (1.8 percent vs. 1.7 percent, P=0.90),
microcephaly (1.6 percent vs. 2.6 percent, P=0.30),
or growth retardation (1.2 percent vs. 1.7 percent,
P=5.00). Data were not analyzed for unenrolled infants born to mothers with a history of epilepsy who
had not taken an anticonvulsant drug during pregnancy, because we could not confirm the maternal history of epilepsy.
DISCUSSION
We found that infants exposed to a single anticonvulsant drug taken by the mother during pregnancy
had a significantly higher frequency of associated
abnormalities than control infants, and that infants
whose mothers had a history of epilepsy but took no
anticonvulsant drugs during pregnancy did not have
an increased rate of these abnormalities. This study
had several strengths: the examiner, who was almost
always unaware of the infants status regarding exposure to drugs, looked systematically for all of the features of the embryopathy associated with exposure to
anticonvulsant drugs in the three groups of infants;
the findings were objective12,24-27; and explicit criteria for the inclusion and exclusion of major malformations were used. Since teratogens cause distinctive
patterns of abnormalities, the statistical analysis took
into account the interrelation of several outcomes.
1136 N Engl J Med, Vol. 344, No. 15 April 12, 2001 www.nejm.org
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ods, such as cephalometric radiography35,36 and dermatoglyphy and radiography of the hands.22 This difference is important, because the hypoplasia of the
midface35,36 associated with hypoplasia of the facial
bones could be a marker for cognitive dysfunction.37
One would predict that some infants exposed to
anticonvulsant drugs have a greater risk of harmful
effects than others because of an underlying genetic
susceptibility. Such an interrelation between genetic
factors and environmental exposure has been suggested in studies of the teratogenicity of maternal cigarette smoking38 and alcohol use.39 In the case of anticonvulsant drugs, a deficiency of the detoxifying
enzyme epoxide hydrolase40,41 and an increase in free
radicals formed by the anticonvulsant drug42 are two
theories of the reason for increased susceptibility. We
predict that the correlations identified in this study
will be much stronger in the more susceptible subgroup of children exposed to anticonvulsant drugs.
Phenytoin, phenobarbital, and carbamazepine are folic acid antagonists, and one postulated mechanism
for their teratogenicity has been the induction of folic acid deficiency.43 However, Hernndez-Daz and
her associates44 recently reported that when pregnant
women taking these anticonvulsant drugs also took
a multivitamin supplement that included folic acid, it
did not reduce the incidence of cardiovascular or urinary tract abnormalities or oral clefts in their infants.
We conclude that exposure in utero to anticonvulsant drugs is associated with a distinctive pattern of
physical abnormalities in infants that are best identified by objective examination. The physical features of
infants exposed to various anticonvulsant drugs are
not the same. We found no evidence that infants born
to women with a history of epilepsy who took no anticonvulsant drugs during pregnancy have an increased
risk of the pattern of physical abnormalities associated
with exposure to anticonvulsant drugs. The occurrence of such embryopathy was correlated with exposure to anticonvulsant drugs, regardless of the underlying maternal illness being treated.
Supported by a grant (NS 24125) from the National Institutes of Health.
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